The sequence listing that is contained in the file named “IOWAP0113US_ST25.txt”, which is 117 KB (as measured in Microsoft Windows®) and was created on Sep. 11, 2014, is filed herewith by electronic submission and is incorporated by reference herein.
I. Field of the Invention
The present invention relates generally to the fields of molecular biology and virology. More particularly, it concerns methods and compositions to treat inflammatory conditions, in particular those resulting from pathologic T-cell activation.
II. Description of Related Art
GB virus C (GBV-C) is a human virus of Flaviviridae family that is most closely related to hepatitis C virus (HCV) (reviewed in Stapleton et al., 2011; Mohr and Stapleton, 2009; Stapleton, 2003). GBV-C infection is common, and about 1% to 4% of US blood donors are viremic at the time of donation. Due to shared route of transmission, the virus is highly prevalent among HIV-infected individuals (up to 42%) (Stapleton et al., 2011; Mohr and Stapleton, 2009; Rey et al., 2000). GBV-C infection is not clearly associated with any disease; however, several studies found an association between persistent GBV-C infection and prolonged survival in HIV-positive individuals (Williams et al., 2004; Nunnari et al., 2003; Xiang et al., 2001; Tillmann et al., 2001; Yeo et al., 2000; Lefrere et al., 1999; Toyoda et al., 1998; Heringlake et al., 1998). GBV-C is lymphotropic, and GBV-C infection modulates multiple host factors that play a critical role in HIV infection including the expression of cytokines, chemokines and their receptors (reviewed in Bhattarai and Stapleton, 2012). The alteration of host factors involved in HIV replication by GBV-C could limit HIV infection and contribute to the protective effect of GBV-C coinfection observed in HIV-positive individuals.
Chronic HIV infection is characterized by persistent immune activation which contributes to T cell depletion, altered cytokine expression and loss of T cell function (reviewed in Pett, 2009; Abrams et al., 2009; Sodora and Silvestri, 2008). Interleukin-2 (IL-2) is a critical cytokine required for T cell activation, proliferation, and function (reviewed in Pett et al., 2010; Nel, 2002). However, IL-2 also induces secretion of proinflammatory cytokines like IL-6, IL-β and tumor necrosis factor alpha (TNF-α) (Fortis et al., 2002; Sereti et al., 2001; Heaton et al., 1993), and is associated with increased levels of inflammatory markers like C-reactive protein (CRP) and D-dimer in the plasma of HIV-infected subjects independent of HIV viral load (Porter et al., 2009). In addition, in vitro activation of peripheral blood mononuclear cells (PBMCs) with IL-2 increases HIV production (Kinter et al., 1995; Morgan et al., 1976). Thus, IL-2 may also promote HIV replication and contribute to HIV associated immune activation Immune activation not only supports HIV replication but it is suggested to be a better predictor of HIV disease progression than plasma HIV viral load (VL) (Giorgi et al., 1999; Hazenberg et al., 2003).
In studies of HIV-infected people, GBV-C viremia is associated with lower surface expression of T cell activation markers compared to GBV-C non-viremic controls independent of HIV VL (Maidana-Giret et al., 2009; Schwarze-Zander et al., 2010; Nattermann et al., 2003). Surface expression of T cell activation markers CD38 and/or CCRS were significantly lower in CD4+ and CD8+ T cells from GBV-C viremic subjects compared to non-viremic controls. Among HIV-infected subjects receiving intravenous IL-2, GBV-C viremic subjects had significantly reduced CD4+ T cell expansion compared GBV-C non-viremic controls (Stapleton et al., 2009) suggesting GBV-C infection may alter T cell activation and IL-2 signaling pathways. In addition, GBV-C produced by peripheral blood mononuclear cells (PBMCs) in vitro was significantly reduced following activation with IL-2 and phytohemagglutinin (PHA) (George et al., 2006) further suggesting an interaction between GBV-C and IL-2. Since IL-2 plays a critical role in HIV infection and disease progression, the effects of GBV-C on IL-2 may contribute to the protective effect of GBV-C coinfection in HIV infected individuals. Previous studies demonstrated that addition of the GBV-C envelope glycoprotein (E2) inhibits HIV replication when added to cells (Mohr and Stapleton, 2009; Koedel et al., 2011; Jung et al., 2007), or when expressed in a CD4+ T cell line (Xiang et al., 2006). However, the full impact of these interactions on immune signaling is not understood.